Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exogenous bradykinin (BK), acting at B2-receptors, enhances norepinephrine (NE) release and exacerbates arrhythmias (VF) in myocardial ischemia/reperfusion. Inhibition of BK formation (with serine proteinase inhibitors) alleviates NE release and VF, whereas prevention of BK degradation (with kininase inhibitors) potentiates them. Yet serine proteinase and kininase inhibitors also prevent the formation of angiotensin (AII), a potent NE-release enhancer. Thus we assessed the respective contribution of AII and BK to NE release and VF by using selective B2- and AT1-receptor antagonists. Isolated guinea pig hearts were subjected to 10- and 20-min global ischemia and 45-min reperfusion. NE overflow (pmol/g) was approximately 8 (exocytotic) and approximately 750 (carrier mediated). VF, associated with carrier-mediated NE release, lasted approximately 2 min. The B2-receptor antagonist Hoe 140 (30 nM) affected neither NE overflow nor VF. In contrast, the AT1-receptor antagonist EXP3174 (100 nM) markedly reduced exocytotic and carrier-mediated NE release and shortened VF. When EXP3174 was combined with Hoe 140, NE overflow and VF were decreased even further. Thus in myocardial ischemia, local AII production contributes to NE release and VF via AT1-receptors. Although BK production increases in myocardial ischemia, the effects of BK on adrenergic nerve terminals are uncovered only when BK half-life is prolonged and/or when AII effects are suppressed.
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PMID:Norepinephrine release and ventricular fibrillation in myocardial ischemia/reperfusion: roles of angiotensin and bradykinin. 1059 38

The renin-angiotensin system (RAS) represents today one of the most strategic targets of the therapy of cardiovascular diseases. During the last 30 years a number of more or less successful approaches to inhibit the activity of the RAS have been attempted. In particular, the use of ACE-inhibitiors has led to significant improvments in the outcom/treatment of hypertension, congestive heart failure, ischemic heart disease and nephropathies. On the other hand, Ace-inhibitors are not specifically targeted to RAS since they interfere with an enzyme with multiple different substrates. Furthermore, the inhibition of ACE does not prevent the formation of angiotensin II through alternative pathways, and thus the inhibition of RAS is often incomplete, especially under pathologic conditions stimulating RAS. For these reasons, the recent discovery of angiotensin II receptors antagonists, which selectively inhibit the action of angiotensin II at the level of the AT1 subtype receptor, is particularly attracting. This article reviews the background, the rationale and some of the clinical findings and potential applications with this new class of compounds.
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PMID:Therapeutic applications of angiotensin II receptor antagonists. 1079 May 92

Based on the reduction of ischemic cardiac events in clinical trials and experimental observations, inhibition of the effects of angiotensin II on coronary microcirculatory function may afford myocardial protection after injury. The immediate effects of intracoronary AT1 receptor blockade with irbesartan were examined in a pig model in the healthy myocardium and in acute ischemia induced by injection of 30-microm microspheres into the left anterior descending coronary artery (LAD). Electron-beam computed tomography was performed for in-vivo quantitative measurements of regional intramyocardial vascular blood volume (V(B)) and perfusion (F(M)), as well as left ventricular ejection fraction (LVEF) and muscle mass. Ratios of V(B) and F(M) in the anterior (LAD-supplied)/ inferior (control) myocardium were generated. At baseline, 0.2 mg/kg irbesartan injected into the LAD increased V(B) and F(M) ratios significantly by 27 +/- 8% and 51 +/- 13%, respectively. After anterior coronary microembolization, V(B) and F(M) ratios were 0.60 +/- 0.05 and 0.51 +/- 0.05, respectively, and were significantly increased by irbesartan (by 24 +/- 10% and by 36 +/- 11%, respectively). After 4 weeks of treatment with oral irbesartan (n = 7) or placebo (n = 7), an improved LVEF (56 +/- 4% v 44 +/- 4%, P = .046) was observed in irbesartan-treated animals, but no difference in LV end-diastolic volumes or muscle mass. Resting V(B) (0.95 +/- 0.06 v 0.76 +/- 0.06; P = .047) and F(M) (0.84 +/- 0.05 v 0.64 +/- 0.04; P = .016) ratios were significantly greater in irbesartan-treated animals. Using adenosine, there was a trend for higher V(B) and F(M) ratios in irbesartan- v placebo-treated animals. Therefore, in a pig model of acute myocardial ischemia, AT1 receptor blockade by irbesartan induced microvascular vasodilation and, ostensibly, conveyed myocardial protection. Long-term treatment with irbesartan resulted in moderate enhancements of resting V(B) and F(M) compared with placebo, suggesting a role for coronary microcirculatory effects of chronic AT1 receptor blockade in preserving LVEF.
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PMID:Effects of acute and chronic angiotensin receptor blockade on myocardial vascular blood volume and perfusion in a pig model of coronary microembolization. 1093 76

The pathogenesis of hypertension in haemodialyzed uraemic patients is multifactorial. The following are involved: sodium and water retention as a result of the impaired excretory capacity of the kidneys, excessively increased activity of the RAAS and sympathetic nerve, increased levels of the vascular constrictor endothelin-1, cumulation of endogenous inhibitors of NO synthesis and reduced formation of vasodepressor factors. As to other factors in the development of hypertension raised intracellular calcium associated with hyperparathyroidism may participate, the stiffness of calcified arteries, erythropoietin treatment and preexisting essential hypertension. Treatment comprises salt restriction below 5 g/day, systematic control of the volume of extracellular fluid by ultrafiltration during every haemodialysis to the level of so-called dry weight and pharmacological treatment in patients where volume control dos not suffice. All drug groups are used. In their selection contraindications are taken into consideration as well as co-morbidity, the dialyzability of antihypertensive drugs and compelling evidence. In patients with a preserved residual diuresis furosemide is administered--125-750 mg/day. Beta-blockers are indicated in patients with IHD, in particular after IM. Calcium blockers are recommended in ventricular hypertrophy and diastolic dysfunction, when beta-blockers are contraindicated and in elderly patients. ACEI indicated in congestive heart failure and left ventricular hypertrophy with systolic dysfunction. Inhibitors of AT1 receptors are an alternative in case of undesirable effects od ACEI. Alpha-blockers and central alpha agonists are used mainly in combinations. In case of failure the haemodialyzation method can be altered or changing the patients to CAPD may be considered. The relationship between BP and the survival of haemodialyzed patients is bimodal. An adverse effect is exerted by a high as well as low BP and in particular by interdialyzation hypotension. The target BP for the haemodialyzed population has not been defined so far. There is, however, evidence that a high BP is independently associated with the de novo development of IHD and MAP above 106 mm Hg with de novo development of cardiac failure. MAP below 98 mm Hg minimalizes the development and progression of left ventricular hypertrophy and MAP below 106 mm Hg the development of heart failure. Long-term survival for 15 and more years is statistically significantly associated with MAP lower than 99 mm Hg.
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PMID:[Hypertension in hemodialyzed uremic patients]. 1095 54

The aim of the study was to investigate the effect of angiotensin-converting enzyme inhibitor enalapril and non-peptide blocker of AT1 receptors losartan on endothelial function of the shoulder artery in patients with congestive cardiac insufficiency. The examination covered 96 patients (mean age 46.71 +/- 4.13) with stable effort angina (functional class II-III) and circulatory insufficiency (NYHA functional class II-III) having end-diastolic left-ventricular volume > 160 ml, left ventricular ejection fraction < 35%, sinus rhythm, cardiothoracal index > 0.55 units. Patients with fibrillar tachyarrhythmia, high grade blocks, pacemaker migration, artificial pacemaker, myocardial infarction were not included in the trial. The patients were randomized into 3 groups 32 patients each. In addition to basic therapy patients of group 1 received long-acting nitrates, digoxin, aspirin and furosemide; group 2--enalapril in daily dose 10 mg; group 3--losartan in daily dose 25 mg. A course of treatment lasted 12 weeks. Endothelial function was assessed by high resolution echography, dopplerography performed before and after temporary occlusion of the shoulder artery and sublingual nitroglycerin. In patients with cardiac insufficiency, accelerated blood flow in the shoulder artery after its temporary occlusion promoted realization of the vasoconstrictory reaction. This was verified as endothelial dysfunction. In the course of the treatment all the patients achieved insignificant increase of the shoulder artery initial diameter. After sublingual intake of nitroglycerin vasodilation was also insignificant. 12-week enalapril and losartan prevented vasoconstriction in the shoulder artery in response to quicker circulation following arterial occlusion. However, higher maximal flow speed did not correspond to the increment in the artery diameter after the occlusion in any group. The flow-induced vasodilation was more pronounced in the enalapril group. Losartan group had a trend to an increase in the inner diameter of the shoulder artery. It is shown that enalapril and losartan in congestive cardiac insufficiency improves endothelium-dependent vasodilation caused by nitroglycerin. Enalapril demonstrated stronger ability than losartan to reverse endothelial dysfunction in patients with cardiac insufficiency resultant from ischemic heart disease.
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PMID:[Prospects of endothelial dysfunction reversion in patients with congestive heart failure]. 1097 40

The cardiac ATP-sensitive potassium (K(ATP)) channel is potentially composed of an inward rectifier potassium channel (Kir6.1 and/or Kir6.2) subunit and the cardiac type of sulfonylurea receptor (SUR2A). We reported that cardiac Kir6.1 mRNA and protein are specifically upregulated in the non-ischemic as well as the ischemic regions in rats with myocardial ischemia, suggesting that humoral and/or hemodynamic factors are responsible for this regulation. In the present study, pretreatment with TCV-116, an angiotensin (Ang) II type 1 receptor antagonist, completely inhibited the upregulation of Kir6.1 mRNA and protein expression in both regions of rat hearts subjected to 60 min of coronary artery occlusion followed by 24 h of reperfusion; whereas pretreatment with lisinopril, an Ang converting enzyme (ACE) inhibitor, partly inhibited this upregulation. Except for rats pretreated with TCV-116, Kir6.1 mRNA levels were positively correlated with those for brain natriuretic peptide (BNP), a molecular indicator of regional wall stress, in both the non-ischemic and the ischemic regions. Plasma Ang II levels were not elevated in rats with control myocardial ischemia compared with sham rats. Thus, the stress-related induction of cardiac Kir6.1 mRNA and protein expression under myocardial ischemia is inhibited by pretreatment with an AT1 antagonist, but also in part by an ACE inhibitor, suggesting that activation of local renin-angiotensin system may play a role.
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PMID:Angiotensin II type 1 receptor blockade abolishes specific K(ATP)channel gene expression in rats with myocardial ischemia. 1111 99

There have been many studies concerning the hemodynamics and physiological mechanisms in ischemic heart disease, little is known about molecular mechanisms during myocardial ischemia in in vivo study. As the signal transduction pathway responsible for myocardial hypertrophy and apoptosis, janus kinase (JAK) and signal transducers and activators of transcription (STAT) are suggested to play an important role. However, whether in vivo activation of JAK-STAT pathway occurs during myocardial ischemia is still unknown. The purpose of this study was to determine whether myocardial JAK or STAT is activated in ischemic heart, and to evaluate the angiotensin blockade on the pathway. Myocardial infarction was produced by ligation of the coronary artery in Wistar rats. After myocardial ischemia, we analysed both activated levels and total amounts of JAK1, JAK2, STAT1 and STAT3 by Western blot analyses at 0, 5, 15, 30, 60, 120 and 240 min. Compared with JAK activities at 0 min, JAK1 activities were significantly increased at 60 and 120 min (3.0- and 3.7-fold, respectively, P<0.01). JAK2 and STAT1 activities of ischemic myocardium were unchanged through the time course. STAT3 activities were increased at 5 min (3.3-fold, P<0.01) and markedly enhanced at 30, 60 and 120 min (4.6-, 7.7- and 8.7-fold, respectively, P<0.01). Pretreatment with imidapril (ACE inhibitor) and candesartan cilexitil (AT1 receptor antagonist) significantly prevented the increase in the phosphorylation of JAK1 at 120 min and STAT3 at 30 and 120 min. Sis-inducing factor (SIF) DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in ischemic myocardium. Imidapril and candesartan cilexitil inhibited the activation of SIF DNA binding at 1 day after coronary ligation. In conclusion, we showed that JAK1 and STAT3 were activated by ischemia from the basal activities in in vivo rat myocardial ischemia model. Imidapril and candesartan cilexitil prevented the increase in phosphorylated JAK1 and STAT3, thereby suggesting that angiotensin II, especially angiotensin II type I receptor, partially mediates activation of myocardial JAK-STAT pathway in acute myocardial ischemia.
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PMID:Myocardial ischemia activates the JAK-STAT pathway through angiotensin II signaling in in vivo myocardium of rats. 1116 35

In myocardial ischemia presynaptic regulation of norepinephrine release may be altered either by ischemic effects on presynaptic receptor signaling or by ischemia-evoked accumulation of endogenous agonists. Because presynaptic receptors are targets of several drugs. such alterations may have pharmacotherapeutic implications. We investigated the effect of brief ischemic periods on presynaptic regulation of norepinephrine release by alpha2-adrenoceptors, beta2-adrenoceptors, adenosine A1-, angiotensin AT1-, and bradykinin B2-receptors in isolated perfused rat hearts. Exocytotic norepinephrine release was evoked by electrical field stimulation. Paired stimulations were performed to compare the pharmacologic intervention (S2) with the release under baseline conditions (S1), and the effects of receptor agonists and antagonists were compared under nonischemic and stop-flow conditions. In summary. during brief myocardial ischemia, presynaptic modulation of norepinephrine release is differentially regulated. Autoinhibitory alpha2-adrenoceptors lose their activity, whereas stimulatory beta2-adrenoceptors are sensitized. Inhibitory adenosine A1-receptors gain importance during ischemia owing to endogenous adenosine formation. Bradykinin- and angiotensin-mediated stimulation of norepinephrine release is not affected under ischemic conditions.
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PMID:Presynaptic regulation of cardiac norepinephrine release in ischemia. 1144 3

We had reported that in the ischemic heart, locally formed bradykinin (BK) and angiotensin II (Ang II) activate B2- and AT1-receptors on sympathetic nerve terminals (SNE), promoting reversal of the norepinephrine (NE) transporter in an outward direction (i.e., carrier-mediated NE release). Although both BK and Ang II contribute to ischemic NE release, Ang II is likely to play a more important role. Since BK is formed by ischemic SNE, we questioned whether cardiac SNE also contribute to local Ang II formation, in addition to being a target of Ang II. SNE were isolated from surgical specimens of human right atrium and incubated in ischemic conditions. These SNE released large amounts of endogenous NE via a carrier-mediated mechanism, as evidenced by the inhibitory effect of desipramine on this process. Moreover, two renin inhibitors, pepstatin-A and BILA 2157 BS, the ACE inhibitor enalaprilat and the AT1-receptor antagonist EXP3174 prevented ischemic NE release. Western blot analysis revealed the presence of renin in cardiac SNE. Renin abundance increased more than three-fold during ischemia. Thus, renin is present in cardiac SNE and is activated during ischemia, eventually culminating in Ang II formation, stimulation of AT1-receptors and carrier-mediated NE release. Our findings uncover a novel autocrine mechanism, by which Ang II, formed at SNE in myocardial ischemia, elicits carrier-mediated NE release by activating prejuntional AT1-receptors.
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PMID:Activation of a renin-angiotensin system in ischemic cardiac sympathetic nerve endings and its association with norepinephrine release. 1248 10

The renin-angiotensin system is activated during myocardial ischemia, and angiotensin II is locally formed in ischemic hearts. At least four angiotensin II receptor subtypes have been identified, the AT1- and the AT2-receptor being the most prominent in the cardiovascular system. AT1-receptor blockade--like inhibition of the angiotensin-converting-enzyme (ACE)--limits infarct size, improves functional recovery following myocardial ischemia and attenuates ventricular remodeling, post-myocardial infarction and the resulting development of heart failure. The potential mechanisms responsible for the cardioprotection by AT1-receptor blockade remain to be elucidated in detail, but appear to involve AT2-receptor activation and--like ACE-inhibitors--bradykinin and prostaglandins. Combined treatment with ACE-inhibitors and AT1-receptor blockers has the potential to further reduce infarct size and improve ventricular remodeling over each monotherapy alone.
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PMID:AT1-receptor blockade in experimental myocardial ischemia/reperfusion. 1294 May 36


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